Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease

Abstract

Dopaminergic cell death in the substantia nigra (SN) is central toParkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/ Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.iron ͉ oxidative stress ͉ substantia nigra ͉ MPTP ͉ 6-hydroxydopamine P arkinson's disease (PD) is the most frequent neurodegenerative movement disorder worldwide. It is characterized by a preferential degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous cytoplasmic inclusions, called Lewy bodies, in the remaining DNs (1). Apart from rare, inherited forms of the disease, the etiology of PD remains unknown. Nevertheless, it seems clear that aging, mitochondrial dysfunction, inflammation, and oxidative imbalance are among the factors contributing to its pathophysiology.A rise in iron content localized in glial cells and DNs of the SNpc has been reported in patients with PD (2, 3). This increase of iron is thought to contribute to DN cell death by catalyzing the production of hydroxyl radicals from hydrogen peroxide, a byproduct in dopamine catabolism, and by promoting fibril formation of ␣-synuclein, the most abundant component of Lewy bodies (4). Neuroprotection achieved by pharmacological or genetic chelation of iron in animal models of PD supports the role of iron in neuronal degeneration in PD (5). Yet, the mechanisms underlying the iron increase have not been elucidated. Transferrin-bound iron (TBI) can be incorporated into cells by an endocytotic process, which is initiated by transferrin receptor 1 (TfR1) ligand binding. Following translocation to early endosomes, iron dissociates from transferrin and is transported to the cytoplasm or directly to the mitochondria. In the brain, iron uptake mediated by TfR participates in iron transport through the blood-brain barrier (6), and the density of TBI-binding sites correlates well with the regional distribution of TfR expression on the luminal surface of endothelial cells. However, TBI-binding sites and TfR expression only loosely correlate with the final steady-state distribution of iron (7). Moreover, TBI-binding sites are decreased in nu...

Human iron transporters

“…Salazar et al [43] have shown that the ?IRE form of DMT1 is increased in the substantia nigra of Parkinson's disease patients. Given that both microcytic mice (gene symbol mk) and Belgrade rats (gene symbol b) have a G185R mutation that impairs DMT1 transport activity [10,11], they could determine whether similar increases in DMT1 were part of an inflammatory etiology of neurodegeneration in two rodent models of Parkinson's disease or were part of a protective response.…”

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

“…Future studies could be profitably directed at testing the possibility for a two step entry process for Mn across biological membranes. It is noteworthy that when MPTP is given to mice, the expression of an isoform of DMT1 increases in the ventral mesencephalon of treated animals concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss (Salazar et al 2008). Thus, DMT1 mutation impairs iron transport and protects against MPTP and 6-hydroxydopamine.…”

Metabolic Changes Induced by Bushenhuoxue Granules on Striatum and Substantia Nigra in a Rat Model of Parkinson’s Disease

“…At present, the aggregation mechanism of iron in the substantia nigra is not very clear, which may be related to the abnormal expression of DMT1 in brain iron regulatory proteins. DMT1 is a transmembrane iron transport protein, participating in the absorption and metabolism of iron and other metal ions in the cell with high expression of in the substantia nigra (Salazar et al 2008). The high expression of DMT1 in PD patients is the same as the abnormal aggregation of brain iron (Zhang et al 2010).…”